PT - JOURNAL ARTICLE AU - Vikas Kumar AU - Richard C. Brundage AU - William S. Oetting AU - Ilo E. Leppik AU - Timothy S. Tracy TI - Differential Genotype Dependent Inhibition of CYP2C9 in Humans AID - 10.1124/dmd.108.020396 DP - 2008 Jul 01 TA - Drug Metabolism and Disposition PG - 1242--1248 VI - 36 IP - 7 4099 - http://dmd.aspetjournals.org/content/36/7/1242.short 4100 - http://dmd.aspetjournals.org/content/36/7/1242.full SO - Drug Metab Dispos2008 Jul 01; 36 AB - The effects of genetic polymorphisms in drug-metabolizing enzymes (e.g., CYP2C9*3) on drug clearance have been well characterized but much less is known about whether these polymorphisms alter susceptibility to drug-drug interactions. Previous in vitro work has demonstrated that genotype-dependent inhibition of CYP2C9 mediated flurbiprofen metabolism, suggesting the possibility of genotype-dependent inhibition interactions in vivo. In the current study, flurbiprofen was used as a probe substrate and fluconazole as a prototypical inhibitor to investigate whether genotype-dependent inhibition of CYP2C9 occurs in vivo. From 189 healthy volunteers who were genotyped for CYP2C9 polymorphisms, 11 control subjects (CYP2C9*1/*1), 9 heterozygous and 2 homozygous for the CYP2C9*3 allele participated in the pharmacokinetic drug interaction study. Subjects received a single 50-mg oral dose of flurbiprofen alone or after administration of either 200 or 400 mg of fluconazole for 7 days using an open, randomized, crossover design. Flurbiprofen and fluconazole plasma concentrations along with flurbiprofen and 4′-hydroxyflurbiprofen urinary excretion were monitored. Flurbiprofen apparent oral clearance differed significantly among the three genotype groups (p < 0.05) at baseline but not after pretreatment with 400 mg of fluconazole for 7 days. Changes in flurbiprofen apparent oral clearance after fluconazole coadministration were gene dose-dependent, with virtually no change occurring in *3/*3 subjects. Analysis of fractional clearances suggested that the fraction metabolized by CYP2C9, as influenced by genotype, determined the degree of drug interaction observed. In summary, the presence of CYP2C9*3 alleles (either one or two alleles) can alter the degree of drug interaction observed upon coadministration of inhibitors. The American Society for Pharmacology and Experimental Therapeutics